Skin Physiology and Architecture
Skin is composed of a myriad of cell types, acting together to maintain overall tissue function. Normal skin physiology and architecture is dependent on the cross talk between these cells, encompassing even more intricate intracellular signaling mechanisms. The delicate balance between biochemical processes is the focus point of all physiological outcomes. This balance is the basis by which the skin exerts its physiological functions including the formation of a pathogenic barrier, modulation of the immune response, serving as an homeostatic barrier (i.e. fluid regulation), and controlling body temperature. Skin pathologies transpire when this balance is compromised and thus non desired physiological routes are expressed.
Skin is a complex tissue organized in distinct layers, namely, the epidermis, dermis and hypodermis, each possessing a different cell characterization and physiological significance (Schaefer and Redelmeier, 1996).
The epidermis is stratified squamous epithelium in which cells undergoing growth and differentiation are strictly compartmentalized (Schaefer and Redelmeier, 1996). In a normal physiologic state, proliferation is confined to the basal cells that adhere to the basement membrane. Differentiation is a spatial process in which basal cells lose their adhesion to the basement membrane, cease DNA synthesis and undergo a series of morphological and biochemical changes. The ultimate maturation step is the production of the cornified layer forming the protective barrier of the skin (Tennenbaum et al., 1991; Wysocki, 1999).
The dermis is mainly composed of matrix fibers and contains various cell types. In addition, all skin appendages, namely, microvasculature, sweat and sebaceous glands, sensory nerves and hair follicles, are localized in the dermis. The dermis has been attributed the supporting role of skin nourishment, maintaining the epidermis and the route by which signals from other parts of the body reach the outer layer (Tennenbaum et al., 1991; Wysocki, 1999).
The hypodermis is the deepest layer of the skin, mainly consisting of adipose cells, also known as the subcutaneous fat layer. Until recently, this layer has been thought to have the role of insulation from the external temperature changes and mechanical support to the upper layers of the skin (Jackson et al., 1993). Only recently, the endocrine significance of fat tissue (Pantanetti et al., 2004; Fliers et al., 2003), specifically the visceral fat tissue, has been acknowledged and identified as playing a role in glucose regulation in diabetes development and progression (Laviola et al., 2006; Maianu, 2001). Moreover, recent publications have identified the potential impact of subcutaneous adipocytes, which secrete several cytokines and growth factors that can affect skin physiology and regeneration (Nakagami et al., 2006).
Insulin Signaling in Skin
The insulin receptor is an insulin-regulated tyrosine kinase. Insulin binding to its receptor results in receptor activation via autophosphorylation of tyrosine residues on several regions of the intracellular β-subunit. Subsequently insulin receptor substrate (IRS) proteins are tyrosine phosphorylated and activated. Tyrosine-phosphorylated IRS-proteins generate downstream signals by the direct binding to the SH2 domains of various signaling proteins. Several enzymes and adaptor proteins have been identified to associate with IRS-1 and IRS-2, including phosphatidylinositol 3-kinase (PI 3-kinase), phosphotyrosine phosphatase SHP2, Grb2, Nck, and Crk. The products of the she gene are also substrates of the insulin receptor since they contain SH2 domains and are tyrosine phosphorylated in response to insulin (White, 1997).
One of the earliest steps in the insulin signaling pathway is the activation of PI 3-kinase. Once activated, the catalytic subunit phosphorylates phosphoinositides at the 3′ position of the inositol ring or proteins at serine residues. PI3K activates downstream molecules such as PtdIns(3,4)P2/PtdIns(3,4,5)P3-dependent kinase 1 (PDK1), which activates serine kinase Akt. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane (Chang et al., 2004; Ishiki and Klip, 2005). Other targets of Akt include mTOR-mediated activation of protein synthesis by PHAS/elf4 and p70s6k and cell survival mechanisms represented by BAD (Bcl-2/Bcl-XL antagonist) and IKK (I-kB Kinase).
Other signal transduction proteins which interact with IRS molecules include Grb2 and SHP2. Flanking its SH2-domain, Grb2 contains two SH3-domains that associate constitutively with proline rich regions in mSOS, a guanine nucleotide exchange factor that stimulates GDP/GTP exchange on Ras. Activated Ras recruits Raf, a serine/threonine kinase to the plasma membrane. Raf activation results in the activation of MEK by phosphorylation of two serine residues. MEK is a dual specificity kinase that activates MAPK (mitogen-activated protein kinase) by both tyrosine and threonine phosphorylation. MAPK acts as an activator of some transcriptional factors (Myc, NF-kB, AP-1), kinases (Rsk), cell survival proteins (Bcl-2, cPL-2) and structural proteins (paxillin) (Taha and Klip, 1999). In addition, insulin stimulates the activation of PKC isoforms in several tissues and cell types. It has also been reported that PKC isoforms may form complexes with the IR and phosphorylate several molecules involved in IR-initiated signaling, inhibiting their function. Among serine/threonine kinases, a crucial role in modulating insulin signals is played by the PKC family members (Farese et al., 2005). For instance, PKCα has been reported to inhibit insulin action in both cellular and animal models. Overexpression of PKCα, has been shown to inhibit insulin signaling in cultured cell systems. Murine models of PKCα gene ablation also exhibit increased sensitivity to insulin, further supporting the concept of the PKCα negative role in insulin signaling by targeting insulin toward degradation. Insulin down stream signaling also involves the specific activation of PKCζ and PKCβ (Formisano et al., 2000). In addition, in skin, insulin was shown to regulate skin proliferation via PKCδ activation and transcriptional regulation of STAT3 (Gartsbein et al., 2006). Insulin also stimulates the formation of a multimolecular complex, including IRS-1 and PKCδ; PKCα inhibits IR/IRS-1 signaling and regulates insulin degradation. Insulin plays an important role in the overall regulation of protein synthesis. Some of the effects of insulin involve changes in mRNAs abundance, but insulin also has important effects on the translation process itself (Patel et al, 2006). Indeed, several initiation and elongation factors are regulated by this hormone, often as a consequence of changes in their states of phosphorylation.
Skin Pathologies in Diabetes
Skin pathologies are a common complication of diabetes, most of which are associated with progression of metabolic defects and some appear with higher incidence in diabetic patients (Wertheimer, 2004; Wertheimer and Enk, 2001). There have been reports indicating specific alteration in skin structure as well as characteristic pathologies of skin associated with the diabetic state. Diabetic patients exhibit dryer, thinner skin with a flakier outer layer; they are more exposed to skin infections caused by both bacterial and fungal sources (Wang and Margolis, 2006; Muller et al., 2005). Moreover, skin elasticity is compromised in diabetic patients similarly to skin in elderly patients, thus, having a higher tendency to break and injure (Yoon et al., 2002; Montagna and Carlisle, 1979; West, 1994). Specifically, thinned skin exhibits a reduction in rete ridges, which undermines the skins' ability to control temperature and fluid homeostasis. Furthermore, it has been demonstrated that the rete ridges serve as the enriched stem cell population of human skin. Therefore, it is clear that the rete ridges attenuation in the structure of diabetic skin results in depletion of the skin stem cell population and leads to severe impairment in skin function and remodeling (Wertheimer, 2004).
Numerous pathologies and disorders specifically associated with diabetic skin pathologies and disorders have been reported in the medical literature. These include (i) necrobiosis lipoidica diabeticorum (NLD)—appears in various stages of diabetes progression. Lesions appear circumscribed, erythematous plaques with a depressed waxy telangiectativ center characteristic of lower extremities; (ii) granuloma annulare—a chronic inflammatory disorder of unknown etiology characterized by erythematous plaques in distal extremities. Lesions are associated with advanced stages of type I diabetes; (iii) diabetic dermopathy—the most common lesion in adult diabetes, associated with the duration of the diabetic state and the appearance of other diabetic complications. Lesions appear as multiple round or oval pink to brown painless plaques; (iv) bullosis diabeticorum—bullous lesions distinctive of long term diabetes, associated with a reduced threshold to blister formation; (v) limited joint mobility—characterized by joint contractures and collagen deposition in the skin. Lesions are thought to result from changes in collagen packing, cross linking and turnover; (vi) scleredema diabeticorum—characterized by a dramatic increase in skin thickness of the posterior neck and upper back; (vii) acanthosis nigricans (AN)—lesions of dark pigmented skin which appears in body folds of the neck and axilla, associated with insulin resistance together with hyperinsulinemia; (viii) acquired perforating dermatosis—lesions characterized by transepithelial elimination of dermal components in perforating skin; (ix) insulin allergy—dermatologic side effects of continuous treatment with insulin and or hypoglycemic agents, often appears as a maculopapular rash or a pain itching erythema at injection sites; and (x) cutaneous skin infections—a common incidence in diabetic patients presenting the leading cause of morbidity and mortality (Wertheimer, 2004).
Another common denominator in these skin pathologies is the effect on the immune system of the skin, which leads to a compromise in the skins' ability to fight off external pathogens (Wang and Margolis, 2006; Muller et al., 2005). In addition, diabetic skin exhibits an impaired immune response to changes in the skin architecture brought by the metabolic complications. Such lesions result from delayed type hypersensitivity, accumulation of activated histocytes (foam cells) in the skin layers or an immune mediated response contributing to the changes in the dermis (Wertheimer, 2004). In addition, diabetic skin has been found to be constantly infected with either microbial or fungal sources due to its reduced ability to effectively react to exogenic infections. These opportunistic agents take advantage of the impaired immune response and pose a constant aggravation to patients (Wang and Margolis, 2006; Muller et al., 2005).
Skin Disorders in Aging
Skin changes are among the most visible signs of aging. Evidence of increasing age include wrinkles and sagging skin. Aging changes in the skin are a group of common conditions and developments that occur as people grow older. With aging, the outer skin layer (epidermis) thins even though the number of cell layers remains unchanged. The number of pigment-containing cells (melanocytes) decreases. Aging skin thus appears thinner, more pale, and translucent. Large pigmented spots, called age spots, liver spots or lentigos, may appear in sun-exposed areas. The subcutaneous fat layer (hypodermis), which provides insulation and padding, thins. This increases the risk of skin injury and reduces the ability to maintain body temperature. More than 90% of all older people have some type of skin disorder.